TGF-β Signaling Is Necessary and Sufficient for Pharyngeal Arch Artery Angioblast Formation

Cell Rep. 2017 Jul 25;20(4):973-983. doi: 10.1016/j.celrep.2017.07.002.


The pharyngeal arch arteries (PAAs) are transient embryonic blood vessels that mature into critical segments of the aortic arch and its branches. Although defects in PAA development cause life-threating congenital cardiovascular defects, the molecular mechanisms that orchestrate PAA morphogenesis remain unclear. Through small-molecule screening in zebrafish, we identified TGF-β signaling as indispensable for PAA development. Specifically, chemical inhibition of the TGF-β type I receptor ALK5 impairs PAA development because nkx2.5+ PAA progenitor cells fail to differentiate into tie1+ angioblasts. Consistent with this observation, we documented a burst of ALK5-mediated Smad3 phosphorylation within PAA progenitors that foreshadows angioblast emergence. Remarkably, premature induction of TGF-β receptor activity stimulates precocious angioblast differentiation, thereby demonstrating the sufficiency of this pathway for initiating the PAA progenitor to angioblast transition. More broadly, these data uncover TGF-β as a rare signaling pathway that is necessary and sufficient for angioblast lineage commitment.

Keywords: Smad; TGF-β; cardiovascular; great vessels; nkx2.5; pharyngeal arch artery; small-molecule screen; zebrafish.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Arteries / cytology*
  • Branchial Region / blood supply*
  • Homeobox Protein Nkx-2.5 / genetics
  • Homeobox Protein Nkx-2.5 / metabolism
  • Signal Transduction
  • Transforming Growth Factor beta / metabolism*
  • Zebrafish
  • Zebrafish Proteins / genetics
  • Zebrafish Proteins / metabolism*


  • Homeobox Protein Nkx-2.5
  • Nkx2.5 protein, zebrafish
  • Transforming Growth Factor beta
  • Zebrafish Proteins